Dysregulated cellular proliferation, genomic instability and survival are hallmarks of all cancers. Normal cellular regulation is a balance of signals that control cell proliferation and programmed cell death (apoptosis). The interplay between these complex processes maintains tissue stability and function. A loss of regulation of these cellular pathways that control cell cycle progression leads to uncontrolled cell growth and tissue homeostasis.
Cell cycle regulation is controlled through an ordered cascade of protein phosphorylation events. Several families of protein kinases that play critical roles in cell cycle progression have been identified. Interestingly, the activity of many of these kinases is increased in human tumors when compared to normal tissue. Whether this is due to increased levels of expression or protein or by changes in expression of co-activators, the ultimate result is a loss of cell cycle regulation.
The Aurora family (Aurora-A, B, C or 2, 1, 3) are serine/threonine kinases that are essential to the regulation and function of mitosis and cytokinesis (summarized in Adams et al., 2001, Trends in Cell Biology 11 (2): 49-54). The expression and activity of Aurora Kinase is cell cycle regulated such that peak activity occurs during mitosis and expression is nearly undetectable in a resting cell. The catalytic domains of the Auroras are highly conserved, with greater than 90% homology, but have distinct subcellular localizations and functions during mitosis and cytokinesis. Aurora Kinase A is localized to centrosomes and spindle poles in mitosis and is required for centrosome segregation and maturation. In contrast, Aurora-B forms a complex with three other proteins, inner centromere protein (INCENP), borealin and survivin, and behaves as a “mitotic passenger protein” (Meraldip P, et al 2004). This chromosomal passenger protein plays a central role in complex functions to chaperone and regulate mitosis and cytokinesis. The movement of the complex from centromeres to the central spindle during anaphase, to the midbody presumably reflects the requirement of Aurora-B to act on different substrates. A range of substrates has been identified for Aurora Kinase A and B with histone 3, a protein involved in chromatin condensation and mitotic entry, being the best characterized. Finally, Aurora C has been shown to be localized to spindle poles during the late stages of mitosis, however very little is known about its overall function (Kimuram M, et al 1999).
Small molecule inhibitors of Aurora Kinases have provided insight into the overall understanding of the role of Auroras in mitotic regulation (Ditchfield C, et al 2003, Hanning E A, et al 2004, and Carpinelli P, et al 2005). Structurally diverse inhibitors promote the same cellular phenotypes and inhibition of histone 3 phosphorylation on serine 10. Additionally, small molecule inhibitors of Aurora Kinase and antisense oligonucleotides have been demonstrated to have an antiproliferative effect on tumor cells. This indicates that inhibition of Aurora Kinase will be useful in the treatment of cancer.